The first long-range aim of the proposed research is to understand the role central nervous system neurotransmitter systems play in the action of psychotropic drug effects and in the maintenance of behavior. We will focus on dopamine (DA), norepinephrine (NE) and 5-hydroxytryptamine (5HT), and their relationship to operant behavior. Feeding, drinking and locomotion will also be studied since they are important components of operant behavior. The actions of neurotransmitters will be modified by drugs and/or neurotoxins. Behavior will be measured using computer-oriented techniques. We will measure changes in neuro-transmitter systems that occur when operant behavior is modified by administration of antidepressant drugs. The goal of this research is to elucidate changes in central nervous system neurochemistry which lead to changes in behavior and which may be involved in the pathophysiology of depression. We will measure the changes in transmitter turnover as a function of behavior that may account for drug-behavior-environment interactions to further understand the relative roles of drugs and the environment in modifications of behavior. The second aim of the proposed research is to determine whether the long-term alternations in monoamine levels and morphological signs of degeneration demonstrated previously in our research on the neurotoxicity of methamphetamine, is also produced by other prescribed or abused anorectics and psychomotor stimulants. Benzphetamine, phenmetrazine, phendimetrazine, phentermine, chlortermine and cocaine will be examined for neurotoxicity. We will study long-term behavioral changes associated with monoaminergic toxicity produced by methamphetamine and hallucinogenic amphetamine analogs, including 3,4-methylenedioxyamphetamine (MDA) and 3,4- methylenedioxymethamphetamine (MDMA), and cocaine. The third aim is to examine in detail the mechanism by which methamphetamine and related drugs produce neurotoxic effects. Our results to date have indicated that 6-hydroxydopamine (6- OHDA) and 5,6-dihydroxytryptamine (5,6-DHT) are formed in brain after a large dose of methamphetamine. We propose to confirm that 6-OHDA and 5,6-DHT are formed in the brain from DA or 5HT using gas chromatography and mass spectrometry. We shall also study the conditions under which this reaction occurs in vitro, ex vivo, and in vivo.